17β-2-oxo-tetrahydrofuranyl)-carbothioic acid ester, -carboxylic acid ester and -carboxylic acid amide androstane derivatives

ABSTRACT

Compounds of the androstane series are described having general formula                    
     and solvates thereof, in which R 1  represents O, S or NH; R 2  individually represents OC(═O)C 1-6  alkyl; R 3  individually represents hydrogen, methyl (which may be in either the α or β configuration) or methylene; or R 2  and R 3  together represent                    
     where R 6  and R 7  are the same or different and each represents hydrogen or C 1-6  alkyl; R 4  and R 5  are the same or different and each represents hydrogen or halogen and  represents a single or a double bond. These compounds and their solvates have use in medicine as anti-inflammatory or anti-allergic agents.

This application is a national stage entry under 35 U.S.C. §371 ofPCT/GB96/03140, filed Dec. 19, 1996.

The present invention relates to novel anti-inflammatory andanti-allergic compounds of the androstane series and to processes fortheir preparation. The present invention also relates to pharmaceuticalformulations containing the compounds and to therapeutic uses thereof,particularly for the treatment of inflammatory and allergic conditions.

Glucocorticosteroids which have anti-inflammatory properties are knownand are widely used for the treatment of inflammatory disorders ordiseases such as asthma and rhinitis. However, glucocorticosteroids ingeneral may suffer from the disadvantage of causing unwanted systemiceffects following administration. WO94113690, WO94/14834, WO92/13873 andWO92/13872 all disclose glucocorticosteroids which are alleged topossess anti-inflammatory activity coupled with reduced systemicpotency.

The present invention provides a novel group of compounds which possessuseful anti-inflammatory activity whilst having little or no systemicactivity. Thus, the compounds of the present invention represent a saferalternative to those known glucocorticoids which have poor side-effectprofiles.

Thus, according to one aspect of the invention, there is provided acompound of formula (I)

and solvates thereof, in which

R₁ represents O, S or NH;

R₂ individually represents OC(═O)C₁₋₆ alkyl;

R₃ individually represents hydrogen, methyl (which may be in either theα or β configuration) or ═CH₂;

or R₂ and R₃ together represent

 wherein R₆ and R₇ are the same or different and each representshydrogen or C₁₋₆ alkyl;

R₄ and R₅ are the same or different and each represents hydrogen orhalogen; and represents a single or a double bond.

In the above definitions, the term “alkyl” as a group or part of a groupmeans a straight chain, or, where available, a branched chain alkylmoiety. For example, it may represent a C₁₋₄ alkyl function asrepresented by methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includesboth compounds of formula (I) and solvates thereof, particularlypharmaceutically acceptable solvates.

It will be appreciated that the invention includes within its scope allstereoisomers of the compounds of formula (I) and mixtures thereof.

In particular the compounds of formula (I) contain an asymmetric centreat the point of attachment of the lactone moiety. Thus, the inventionincludes within its scope both diastereoisomers at this asymmetriccentre and mixtures thereof.

Diastereoisomers and mixtures thereof at the asymmetric centre formedwhen R₂ and R₃ together represent

and R₆ and R₇ are different are also included within the scope of thepresent invention.

R₁ can be bonded to the alpha, beta or gamma carbon atoms of the lactonegroup,

however, compounds of formula (I) in which R₁ is bonded to the alphaatom are generally preferred.

A preferred group of compounds of the invention are compounds of formula(I) in which R₁ represents O or S, especially S.

A further preferred group of compounds of the invention are compounds offormula (I) in which R₂ individually represents OC(═O)C₁₋₆ alkyl, morepreferably OC(═O)C₁₋₃ alkyl, especially OC(═O)ethyl. Compounds withinthis group in which R₃ is methyl are generally preferred.

Another preferred group of compounds are compounds of formula (I) inwhich R₂ and R₃ together represent

wherein R₆ and R₇ are the same or different and each represents hydrogenor C₁₋₆ alkyl, particularly hydrogen or C₁₋₃ alkyl, especially hydrogen,methyl or n-propyl.

Compounds of formula (I) in which R₄ and R₅, which can be the same ordifferent, each represents hydrogen, fluorine or chlorine, particularlyhydrogen or fluorine, are preferred. Especially preferred are compoundsin which both R₄ and R₅ are fluorine.

A particularly preferred group of compounds of the present invention arecompounds of formula (I) in which R₁ is S; R₂ is OC(═O)C₁₋₆ alkyl,particularly OC(═O)C₁₋₃ alkyl, especially OC(═O)ethyl; R₃ is methyl; R₄and R₅, which can be the same or different, each represents hydrogen orfluorine, especially fluorine, and represents a single or a double bond.

A further particularly preferred group of compounds of the invention arecompounds of formula (I) in which R₁ is S; R₂ and R₃ together represent

wherein R₆ and R₇ are the same or different and each represents hydrogenor C₁₋₆ alkyl, particularly hydrogen or C₁₋₃ alkyl, especially hydrogen,methyl or n-propyl; R₄ and R₅ which can be the same or different eachrepresents hydrogen or fluorine, especially fluorine; and represents asingle or a double bond. The R-isomers of compounds within this group inwhich R₆ and R₇ are different are preferred.

It is to be understood that the present invention covers allcombinations of particularly and preferred groups referred tohereinabove.

Compounds of formula (I) include:

17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

17α-Acetyloxy-6α,9β-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

9α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

6α,9β-Difluoro-11β-droxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(5-oxo-tetrahydro-furan-2-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-4-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-5-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-5-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;

16α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester,

16α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-4-yl) amide;

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid (5-oxo-tetrahydro-furan-2-yl) ester; and solvates thereof.

Preferred compounds of formula (I) include:

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;

and solvates thereof.

It will be appreciated that each of the above compounds of formula (I)includes the individual R and S diastereoisomers at the asymmetriccentre at the point of attachment of the lactone moiety as well as themixtures thereof. It will further be appreciated that the compounds offormula (I) may include the individual R and S diastereoisomers at theasymmetric centre formed when R₂ and R₃ together represent

wherein R₆ and R₇ are different, as well as mixtures thereof.

Thus, the individual R and S diastereoisomers isolated such as to besubstantially free of the other diastereoisomer ie pure and mixturesthereof are included within the scope of the present invention. Anindividual R or S diastereoisomer isolated such as to be substantiallyfree of the other diastereoisomer ie pure will preferably be isolatedsuch that less than 10% preferably less than 1% especially less than0.1% of the other diastereoisomer is present.

The compounds of formula (I) have potentially beneficialanti-inflammatory or anti-allergic effects, particularly upon topicaladministration, demonstrated by, for example, their ability to bind tothe glucocorticoid receptor and to illicit a response via that receptor.Hence, the compounds of formula (I) are useful in the treatment ofinflammatory and/or allergic disorders. Further, compounds of formula(I) possess the advantage of having little or no systemic activity.Therefore, the compounds of the invention may represent a saferalternative to those known anti-inflammatory glucocorticoids which havepoor side effect profiles.

Examples of disease states in which the compounds of the invention haveutility include skin diseases such as eczema, psoriasis, allergicdermatitis neurodermatitis, pruritis and hypersensitivity reactions;inflammatory conditions of the nose, throat or lungs such as asthma(including allergen-induced asthmatic reactions), rhinitis (includinghayfever), nasal polyps, chronic obstructive pulmonary disease,interstitial lung disease, and fibrosis; inflammatory bowel conditionssuch as ulcerative colitis and Crohn's disease; and auto-immune diseasessuch as rheumatoid arthritis.

Compounds of the invention may also have use in the treatment ofconjunctiva and conjunctivitis.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

As mentioned above, compounds of formula (I) are useful in human orveterinary medicine, in particular as anti-inflammatory andanti-allergic agents.

There is thus provided as a further aspect of the invention a compoundof formula (I) or a physiologically acceptable solvate thereof for usein human or veterinary medicine, particularly in the treatment ofpatients with inflammatory and/or allergic conditions.

According to another aspect of the invention, there is provided the useof a compound of formula (I) or physiologically acceptable solvatethereof for the manufacture of a medicament for the treatment ofpatients with inflammatory and/or allergic conditions.

In a further or alternative aspect, there is provided a method for thetreatment of a human or animal subject with an inflammatory and/orallergic condition, which method comprises administering to said humanor animal subject an effective amount of a compound of formula (I) orphysiologically acceptable solvate thereof.

The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions comprising acompound of formula (I) or physiologically acceptable solvate thereoftogether, if desirable, in admixture with one or more physiologicallyacceptable diluents or carriers.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulatedfor oral, buccal, sublingual, parenteral, local or rectaladministration, especially local administration.

Local administration as used herein, includes administration byinsufflation and inhalation. Examples of various types of preparationfor local administration include ointments, lotions, creams, gels,foams, preparations for delivery by transdermal patches, powders,sprays, aerosols, capsules or cartridges for use in an inhaler orinsufflator or drops (e.g. eye or nose drops), solutions/suspensions fornebulisation, suppositories, pessaries, retention enemas and chewable orsuckable tablets or pellets (e.g. for the treatment of aphthous ulcers)or liposome or microencapsulation preparations.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

Spray compositions may for example be formulated as aqueous solutions orsuspensions or as aerosols delivered from pressurised packs, such as ametered dose inhaler, with the use of a suitable liquefied propellant.Aerosol compositions suitable for inhalation can be either a suspensionor a solution and generally contain a compound of formula (I) and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. The aerosolcomposition may optionally contain additional formulation excipientswell known in the art such as surfactants e.g. oleic acid or lecithinand cosolvents e.g. ethanol.

Advantageously, the formulations of the invention may be buffered by theaddition of suitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of forexample geiatine, may be formulated containing a powder mix forinhalation of a compound of the invention and a suitable powder basesuch as lactose or starch. Each capsule or cartridge may generallycontain between 20 μg-10 mg of the compound of formula (I).Alternatively, the compound of the invention may be presented withoutexcipients such as lactose.

The proportion of the active compound of formula (I) in the localcompositions according to the invention depends on the precise type offormulation to be prepared but will generally be within the range offrom 0.001 to 10% by weight. Generally, however for most types ofpreparations advantageously the proportion used will be within the rangeof from 0.005 to 1% and preferably 0.01 to 0.5%. However, in powders forinhalation or insufflation the proportion used will be within the rangeof from 0.1 to 5%.

Aerosol formulations are preferably arranged so that each metered doseor “puff” of aerosol contains 20 μg-2000 μtg, preferably about 20 μg-500μg of a compound of formula (I). Administration may be once daily orseveral times daily, for example 2, 3, 4 or 8 times, giving for example1, 2 or 3 doses each time. The overall daily dose with an aerosol willbe within the range 100 μg-10 mg preferably, 200 μg-2000 μg. The overalldaily dose and the metered dose delivered by capsules and cartridges inan inhaler or insufflator will generally be double those with aerosolformulations.

Topical preparations may be administered by one or more applications perday to the affected area; over skin areas occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For internal administration the compounds according to the inventionmay, for example, be formulated in conventional manner for oral,parenteral or rectal administration. Formulations for oraladministration include syrups, elixirs, powders, granules, tablets andcapsules which typically contain conventional excipients such as bindingagents, fillers, lubricants, disintegrants, wetting agents, suspendingagents, emulsifying agents, preservatives, buffer salts, flavouring,colouring and/or sweetening agents as appropriate. Dosage unit formsare, however, preferred as described below.

Preferred forms of preparation for internal administration are dosageunit forms i.e. tablets and capsules. Such dosage unit forms containfrom 0.1 mg to 20 mg preferably from 2.5 to 10 mg of the compounds ofthe invention.

The compounds according to the invention may in general may be given byinternal administration in cases where systemic adreno-cortical therapyis indicated.

In general terms preparations, for internal administration may containfrom 0.05 to 10% of the active ingredient dependent upon the type ofpreparation involved. The daily dose may vary from 0.1 mg to 60 mg, e.g.5-30 mg, dependent on the condition being treated, and the duration oftreatment desired.

Slow release or enteric coated formulations may be advantageous,particularly for the treatment of inflammatory bowel disorders.

The pharmaceutical compositions according to the invention may also beused in combination with another therapeutically active agent, forexample, a β₂ adrenoreceptor agonist, an anti-histamine or ananti-allergic. The invention thus provides, in a further aspect, acombination comprising a compound of formula (I) or a physiologicallyacceptable solvate thereof together with another therapeutically activeagent, for example, a β₂-adrenoreceptor agonist, an anti-histamine or ananti-allergic.

The combination referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalformulations. Appropriate doses of known therapeutic agents will bereadily appreciated by those skilled in the art.

The compounds of formula (I) and solvates thereof may be prepared by themethodology described hereinafter, constituting a further aspect of thisinvention.

Thus, according to a first process (A), a compound of formula (I) may beprepared by treating a compound of formula (II)

in which R₂, R₃, R₄, R₅ and are as defined hereinbefore for compounds offormula (I) and X represents OH or an activated derivative thereof suchas a triazole or a mixed anhydride, with a compound of formula (III)

and salts thereof, in which

Z represents OH, NH₂ or SH.

Thus, a compound of formula (II) wherein X represents OH may beactivated with an activating agent such as a triazole e.g.1-hydroxy-benzotriazole and a carbodiimide such as1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride in a polarsolvent such as dimethylformamide, conveniently at elevated temperaturese.g. about 100° C., and under an inert atmosphere such as nitrogen orthe like, to form an activated derivative of the compound of formula(II), such as a triazole derivative e.g. a benzotriazole derivative offormula (IV)

(in which R₂, R₃, R₄, R₅ and are as defined hereinbefore).

The activated derivative, which may be isolated if required, is reactedwith a compound of formula (III) wherein Z represents NH₂, SH or OH toform the desired compound of formula (I).

It will be appreciated by those skilled in the art that the couplingreaction may take place in one step without the isolation of theactivated derivative if a compound of formula (III) is present during oradded following activation. Alternatively, the activated derivative maybe isolated and then subsequently treated with a compound of formula(III) to form the desired compound of formula (I).

Both methods are included within the scope of the present invention.

Compounds of formula (I) may also be prepared according to the aboveprocess (A) by coupling a compound of formula (II) wherein X representsOH with a compound of formula (III) wherein Z represents SH, OH or NH₂via an intermediate mixed anhydride, for example, a mixed phosphateanhydride such as a compound of formula (V) as described by Kertesz andMarx in the Journal of Organic Chemistry, 1986, 51, 2315-2328.

Thus, a compound of formula (II) wherein X represents OH may beactivated with an activating agent, such as diethylchlorophosphate inthe presence of a base such as a tertiary amine e.g. triethylamine andin a suitable solvent such as a chlorinated solvent e.g. dichloromethaneto form an activated derivative of the compound of formula (II) e.g. adiethylphosphate mixed anhydride derivative of formula (V)

(in which R₂, R₃, R₄, R₅ and are as defined hereinbefore).

The activated derivative, which may be isolated if required, is reactedwith a compound of formula (III) wherein Z represents SH, OH or NH₂ toform the desired compound of formula (I).

It will be appreciated by those skilled in art that the couplingreaction may take place without the isolation of the activatedderivative if a compound of formula (III) is present during or addedfollowing activation. Alternatively, the activated derivative may beisolated and then subsequently treated with a compound of formula (III)to form the desired compound of formula (I).

Both methods are included within the scope of the present invention.

Compounds of formula (I) wherein R₁ represents O or S may also beprepared according to a second process (B) in which a compound offormula (II) in which R₂, R₃, R₄, R₅ and are as defined hereinbefore andX represents OH or SH or their corresponding salts, is treated with acompound of formula (VI) or formula (VII)

in which Q represents a suitable leaving group (such as Cl, Br, OSO₂Awherein A is, for example CH₃, CF₃, p-CH₃C₆H₄), under standard methods.

The above general process (B) employing compounds of formula (VI) can beused to prepare compounds of formula (I) in which R₁ is linked to thealpha, beta, or gamma carbon atoms of the lactone group.

Compounds of formula (I) wherein R₁ represents O or S may be preparedaccording to the above process (B) by alkylation of a compound offormula (II) wherein X represents OH or SH respectively, with a compoundof formula (VI) wherein Q represents a suitable leaving group usingmethods known in the art, or an adaptation of those methods.

Thus, for example, a compound of formula (I) wherein R₁ represents O maybe prepared by alkylation of a compound of formula (II) wherein Xrepresents OH conveniently in the form of an appropriate salt (such asalkali metal e.g. sodium or quarternaryammonium salt) with a compound offormula (VI) wherein Q represents a suitable leaving group, preferablychlorine, bromine or mesylate. The alkylation reaction is preferablycarried out in the presence of a solvent, suitably a polar solvent,under inert conditions, for example, nitrogen or the like, convenientlyat a temperature of between about 0° C. to 100° C. Suitable polarsolvents may include acetone, dimethylformamide, dimethyl acetamide,dimethylsulphoxide, dichloromethane or chloroform.

Similarly, compounds of formula (I) wherein R₁ represents S can beprepared according to the above process (B) by alkylation of a compoundof formula (II) wherein X represents SH with a compound of formula (VI)wherein Q represents a suitable leaving group by adaptation of themethods described by Phillipps et al, Journal of Medicinal Chemistry,1994, 37, 3717-3729. Thus, a compound of formula (I) wherein R₁represents S may be prepared by alkylation of the corresponding compoundof formula (II) wherein X represents SH conveniently in the form of anappropriate salt (such as alkali metal e.g. sodium orquarternaryammonium salt) with a compound of formula (VI) wherein Zrepresents a suitable leaving group as described hereinabove for similaralkylation reactions.

Alternatively, compounds of formula (I) wherein R₁ represents O or S maybe prepared according to the above process (B) by alkylation of acompound of formula (II) wherein X represents OH or SH with a compoundof formula (VI) wherein Q represents OH under Mitsunobu conditions usingtriphenylphosphine and a dialkyl azodicarboxylate, or by using Vilsmeiermethodology as described by Barrett and Procopiou in the Journal of theChemical Society, Chemical Communications, 1995, 1403-1404.

A compound of formula (I) wherein R₁ represents S and is bonded to thebeta carbon atom of the lactone group may also be prepared by reactingthe corresponding compound of formula (II) wherein X represents SH witha compound of formula (VII). For example, by Michael addition of thecompound of formula (II) with the compound of formula (VII) in thepresence of a base such as potassium carbonate and in a suitable solventsuch as dimethylforamide.

Compounds of formula (I) may also be prepared from other compounds offormula (I) thereof using conventional interconversion procedures suchas transacetalisation, epimerisation or esterification. Thus, a processfor preparing a compound of formula (I) by interconversion of anothercompound of formula (I) (process C) constitutes a further aspect of thepresent invention.

Compounds of formula (I) having a 1,2 single bond may be prepared bypartial reduction of the corresponding 1,2 double bond compound byconventional methods. Thus, for example, by hydrogenation of thecorresponding compound of formula (I) or of an intermediate used for thepreparation of a compound of formula (I) using a palladium catalyst,conveniently in a suitable solvent e.g. ethyl acetate or preferably byusing tris(triphenylphosphine) rhodium (I) chloride (known asWilkinson's catalyst), conveniently in a suitable solvent such astoluene, ethyl acetate or ethanol.

It will be appreciated by those skilled in the art that it may bedesirable to use protected derivatives of intermediates used in thepreparation of compounds of formula (I). Thus, the above processes mayrequire deprotection as an intermediate or final step to yield thedesired compound. Thus, according to another process (D), a compound offormula (I) may be prepared by subjecting a protected derivative of acompound of formula (I) to reaction to remove the protecting group orgroups present, constituting a further aspect of the present invention.

Protection and deprotection of functional groups may be effected usingconventional means. Thus, hydroxyl groups may be protected using anyconventional hydroxyl protecting group, for example, as described inProtective Groups in Organic Chemistry, Ed. J. F. W. McOmie (PlenumPress, 1973) or Protective Groups in Organic Synthesis by Theodora W.Green (John Wiley and Sons, 1991).

Examples of suitable hydroxyl protecting groups includes groups selectedfrom alkyl (e.g. t-butyl or methoxymethyl), aralkyl (e.g. benzyl,diphenylmethyl or triphenylmethyl), heterocyclic groups such astetrahydropyranyl, acyl (e.g. acetyl or benzoyl) and silyl groups suchas trialkylsilyl (e.g. t-butyidimethylsilyl). The hydroxyl protectinggroups may be removed by conventional techniques. Thus, for examplealkyl, silyl, acyl and heterocyclic groups may be removed by solvolysis,e.g. by hydrolysis under-acidic or basic conditions. Aralkyl groups suchas triphenylmethyl may be similarly be removed by solvolysis, e.g. byhydrolysis under acidic conditions. Aralkyl groups such as benzyl may becleaved by hydrogenolysis in the presence of a Noble metal catalyst suchas palladium-on-charcoal.

The compounds of formulae (II), (III), (IV), (V), (VI) and (VII) areeither generally known compounds or may be prepared by methods analogousto those described in the art for preparing the known compounds offormula (II), (III), (IV), (V), (VI) and (III) or may be prepared by themethods described herein. Novel compounds of formulas (II), (III), (IV),(V) and (VI) form yet a further aspect of the present invention.

For example, the compounds of formula (II) wherein X represents OH canbe prepared by oxidation of an appropriate 21-hydroxy-20-keto-pregnaneof formula (VIII)

(in which R₂, R₃, R₄, R₅ and are as defined hereinbefore) using, forexample, the methodology described by Kertesz and Marx, Journal ofOrganic Chemistry, 1986, 51, 2315-2328.

Compounds of formula (VIII) are commercially available, for example,fluocinolone acetonide, budesonide and triamcinolone acetonide areavailable from Sigma-Aldrich, or can be prepared from the commerciallyavailable compounds of formula (VIII) by, for example, thetransacetalisation methods described in EP0262108 and by partialreduction of the 1,2 double bond compounds by the methods describedherein. Alternatively, compounds of formula (VIII) can be prepared fromcommercially available 17α-hydroxyl derivatives of compounds of formula(VIII), for example, betamethasone, flumethasone prednisolone,beclomethasone, and dexamethasone available from Sigma-Aldrich, byesterification of the 17α-hydroxyl group according to the methoddescribed by Gardi et al, Tetrahedron Letters, 1961, 448. Novelcompounds of formula (VIII) form yet a further aspect of the presentinvention.

Compounds of formula (II) wherein X represents SH can be prepared by theapplication or adaptation of known methods, for example, using methodsdescribed by Phillipps et al, Journal of Medicinal Chemistry, 1994, 37,3717-3729.

Compounds of formula (III), (VI) and (VII) are commercially availablefrom Sigma-Aldrich or may be readily prepared by application oradaptation of known methods. For example, compounds of formula (III)wherein Z is SH can be prepared by methods described in G. Fuchs inArk-Kemi, 1966, 26, 111 and 1968, 29, 379; compounds of formula (III)wherein Z is β-amino can be prepared by the methods described in G. J.McGarvey et al. Tetrahedron Letters, 1983, 24, 2733; the chiral α-OHcompounds of formula (III) can be prepared by the methods described inKenne et al. J. Chem. Soc. Perkin Trans. I, 1988, 1183; and the α-chlorocompound of formula (VI) by the methods described in P Four et al, J.Org. Chem. 1981, 46, 4439.

Individual isomers of formula (I) at the point of attachment of thelactone moiety may either be prepared from starting materials having thedesired stereochemistry or by epimerisation, resolution fractionalcrystallisation or chromatography (e.g. HPLC separation) at anappropriate stage in the synthesis of the required compounds of formula(I) using conventional means.

Thus, for example, it will be appreciated that synthesis employing aracemic mixture of compounds of formula (III) or (VI) will affordcompounds of formula (I) as a mixture of diastereoisomers, which maythen be separated. Alternatively, the individual diastereoisomers may beprepared by employing compounds of formula (III) or (VI) inenantiomerically pure form.

Similarly, compounds of formula (I) in which R₂ and R₃ togetherrepresent

wherein R₆ and R₇ are different, may exist in the R and Sdiastereoisomeric forms. Synthesis of such compounds may bestereospecific to yield individual diastereoisomers. Thus, for example,the R-diastereoisomer of a compound of formula (I) wherein R₆ representsH and R₇ represents n-propyl may be conveniently prepared bytransacetalisation of the corresponding 16α,17α-isopropylidenedioxyderivative with butyraldehyde in the presence of an acid catalyst, suchas perchloric acid, as described in EP0262108. The transacetalisationreaction may be performed at an intermediate stage or after introductionof the lactone group.

Solvates (e.g. hydrates) of a compound of formula (I) may be formedduring work-up procedure of one of the aforementioned process steps.Thus, the compounds of formula (I) may be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

The following Examples illustrate the invention but do not limit theinvention in any way.

EXAMPLES

General

Melting points were determined on a Kofler block and are uncorrected.¹H-nmr spectra were recorded at 250 or 400 MHz and the chemical shiftsare expressed in ppm relative to tetramethylsilane. The followingabbreviations are used to describe the multiplicities of the signals: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd(doublet of doublets), dt (doublet of triplets) and b (broad).MS(TSP+ve) and MS(ES+ve) refer to mass spectra run in positive modeusing thermospray or electrospray techniques respectively. HRMS (ES+ve)refers to high resolution eiectrospray mass spectrum run in positivemode. TLC (thin layer chromatography) was performed on Merck Kieselgel60 F₂₅₄ plates and column chromatography was performed on MerckKieselgel 60 (Art. 7734 or 9385). PLC (preparative layer chromatography)was performed on Whatman silica plates. Preparative HPLC (highperformance liquid chromatography) was performed on a Gilson MedicalElectronics system using the stationary phase indicated in the example.DMF is used as an abbreviation for anhydrous N,N-dimethylformamide.Organic solutions were dried over anhydrous magnesium sulfate.

Where mixtures of isomers resulting from the asymmetric centre in thelactone group have been prepared, these isomers may be separated byconventional chromatography on silica and assigned as isomers A and Brespectively in order of elution from the column.

Intermediate 1

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carboxylicacid

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (1.36 g, 3 mmol) was added to a solution of Wilkinson's catalyst(150 mg) in ethyl acetate (100 ml) and the resultant solution stirredunder an atmosphere of hydrogen until hydrogenation was complete. Theprogress of the reaction was followed by HPLC. The solution was thenextracted with saturated aqueous sodium bicarbonate (4×50 ml) and thecombined aqueous layers washed with ethyl acetate (75 ml) beforeacidification of the aqueous layer to pH1 with conc. hydrochloric acid.This was then extracted with ethyl acetate (75 ml) and the extract driedand evaporated to yield the title compound as a solid (1.14 g, 84%): mp.216-218° C.; MS (TSP+ve) m/z 455 [MH]⁺; NMR δ (DMSO d₆) includes 12.50(1H, bs), 5.80 (1H, s), 5.60 and 5.40 (1H, 2m), 5.13 (1H, m), 3.18 (1H,m), 2.34 (2H, q, J 8 Hz), 1.48 (3H, s), 1.00 (6H, s and t, J 8 Hz), 0.85(3H, d, J 9 Hz).

Intermediate 2

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioicacid S-(N,N-dimethylcarbamic acid anhydride)

Triethylamine (378 μl, 2.72 mmol) was added to a suspension of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carboxylicacid, (Intermediate 1, 825 mg, 1.81 mmol) in dry dichloromethane (12 ml)under nitrogen. A clear solution was obtained andN,N-dimethylthiocarbamoyl chloride (669 mg, 5.43 mmol) was then added inone portion, the solution stirred at room temperature and progress ofthe reaction followed by HPLC. On completion the reaction was dilutedwith ethyl acetate (50 ml) and washed successively with 1M hydrochloricacid (30 ml), 5% sodium bicarbonate solution (30 ml) and brine solution(30 ml) before drying and evaporating to yield the crude product as afoam. This was purified by preparative layer chromatography on silicagel, eluting with dichloromethanediethyl ether (5:2) to give the titlecompound as a crystalline solid (507 mg, 58%): mp. 189-191° C.; IRν_(max) (KBr) 3363, 1750, 1722, 1669, 1651 cm⁻¹; NMR δ (CDCl₃) includes6.13 (1H, s), 5.20 and 5.35 (1H, 2m), 4.37 (1H, m), 3.33 (1H, m), 3.08and 3.16 (6H, 2s), 2.42 (2H, q, J 7 Hz), 1.51 (3H, s), 1.14-1.20 (6H, sand t, J 7 Hz), 0.98 (3H, d, J 7 Hz). Found: C, 59.53; H, 7.11; N, 2.40;S, 5.69. C₂₇H₃₇F₂NO₆S requires C, 59.87; H, 6.89; N, 2.59; S, 5.92%).

Intermediate 3

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioicacid

A mixture of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioicacid S-(N,N-imethylcarbamic acid anhydride) (Intermediate 2, 490 mg,0.905 mmol) in diethylamine (5 ml) was heated under reflux in a nitrogenatmosphere. The progress of the reaction was followed by TLC analysisand when complete the reaction mixture was poured into an ice-cooledmixture of 3.5M hydrochloric acid (60 ml) and ethyl acetate (40 ml). Theorganic phase was separated, washed with water (30 ml) and extractedwith 5% sodium carbonate solution (3×20 ml). The combined basic extractswere then layered with ethyl acetate (40 ml) and adjusted to pH1 with 6Mhydrochloric acid. The organic phase was separated, dried and evaporatedto give the title compound as a solid (190 mg, 45%): mp. 147-151° C.; MS(TSP+ve) m/z 471 [MH]⁺; NMR δ (CDCl₃) includes 6.13 (1H, s), 5.38 and5.19 (1H, 2m), 4.40 (1H, m), 3.28 (1H, m), 2.43 (2H, q, J 7 Hz), 1.52(3H, s), 1.17 (3H, t, J 7 Hz) 1.13 (3H, s), 0.99 (3H, d, J 7 Hz).

Intermediate 4

Methanesulfonic acid 2-oxo-tetrahydro-furan-3R-yl ester

To a stirring solution of (R)-3-hydroxy-2-oxo-tetrahydro-furan (400 mg,3.92 mmol) and triethylamine (601 μl, 4.31 mmol) in anhydrousdichloromethane (15 ml) at 0° C. under a nitrogen atmosphere was addedmethanesulfonyl chloride (334 μl, 4.31 mmol). The resulting mixture wasstirred at 0° C. for 0.25 h and at 21° C. for 2.5 h. Further quantitiesof triethylamine (109 μl, 0.78 mmol) and methanesulfonyl chloride (61μl, 0.78 mmol) were added and the mixture stirred for 1.5 h. Thereaction mixture was poured into water (20 ml) and the separated aqueouslayer was extracted with dichloromethane (20 ml). The combined organiclayers were washed with saturated sodium bicarbonate solution (20 ml)and saturated brine (20 ml) then dried over anhydrous magnesium sulfate.The solvent was removed under reduced pressure yielding a yellow residuewhich was purified by flash column chromatography on silica gel usingethyl acetate:cyclohexane (3:2) as eluent. Removal of the solvent fromappropriate fractions under reduced pressure gave the title compound asa white crystalline solid (214 mg, 30%): mp 69-72° C.; MS (TSP+ve) m/z198 (M+NH₄)⁺; IR ν_(max) (KBr) 1774, 1363 cm⁻¹; NMR δ (CDCl₃) 5.33 (1H,t, J 9 Hz), 4.53 (1H, dt, J 9 and 3.5 Hz), 4.43-4.28 (1H, m), 3.30 (3H,s), 2.88-2.72 (1H, m), 2.66-2.47 (1H, m). (Found: C, 33.53; H, 4.16; S,17.35. C₅H₈O₅S.0.05H₂O requires C, 33.17; H, 4.51; S, 17.71%).

Intermediate 5

Methanesulfonic acid 2-oxo-tetrahydro-furan-3S-yl ester

Methanesulfonyl chloride (1.67 ml, 21.56 mmol) was added to a stirredsolution of (S)-3-hydroxy-2-oxo-tetrahydrofuran (2 g, 19.6 mmol),4-N,N-dimethylaminopyridine (240 mg, 1.96 mmol) anddiisopropylethylamine (3.76 ml, 21.56 mmol) in dry dichloromethane (20ml), under nitrogen, at −40° C. The mixture was stirred for 30 minutesand then allowed to warm up to room temperature, then it was washed with2M hydrochloric acid solution (50 ml), dried and evaporated to a solid.The crude product was purified by flash chromatography on silica gel,eluting with ethyl acetate-cyclohexane (1:1). Trituration withdiethylether and drying in vacuo afforded the title compound as acrystalline white solid (2.23 g, 63%): mp. 70-75° C.; NMR δ (CDCl₃) 5.33(1H, t, J 8 Hz), 4.53 (1H, dt, J 9 and 2 Hz), 4.34 (1H, dt, J 10 and 6Hz), 3.28 (3H, s), 2.86-2.72 (1H, m), 2.65-2.47 (1H, m).

Intermediate 6

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(N,N-dimethylcarbamic acid anhydride)

Triethylamine (550 ∞l, 3.94 mmol) was added to a suspension of16α,17α-(R-butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid (1.345 g, 2.96 mmol) in dry dichloromethane (20 ml) under nitrogen.A clear solution was obtained and N,Ndimethylthiocarbamoyl chloride(1.11 g, 9 mmol) was then added in one portion, the solution stirred atroom temperature and progress of the reaction followed by HPLC. Oncompletion the reaction mixture was concentrated under reduced pressureand the residue was dissolved in ethyl acetate (50 ml) and washedsuccessively with 2M hydrochloric acid (30 ml), 5% sodium bicarbonatesolution (30 ml) and brine solution (30 ml) before drying andevaporating to yield the crude product as a foam. This was purified bycolumn chromatography on silica gel, eluting withacetone-dichloromethane (1:9) to give the title compound as a foam (840mg, 52%): MS (ES+ve) m/z 542 (MH)⁺; NMR δ (CDCl₃) includes 6.15 (1H, s),5.37 and 5.18 (1H, 2m), 4.86 (1H, d, J 5 Hz), 4.78 (1H, t, J 4 Hz), 4.40(1H, m), 3.14 and 3.09 (6H, 2s), 1.52 (3H, s), 1.04 (3H, s), 0.96 (3H,d, J 7 Hz).

Intermediate 7

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid

A mixture of16α,17α-(R-butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(N,N-dimethylcarbamic acid anhydride (Intermediate 6; 830 mg,1.53 mmol) in diethyiamine (8 ml) was heated under reflux in a nitrogenatmosphere. The progress of the reaction was followed by TLC analysisand when complete the reaction mixture was concentrated under reducedpressure and the residue was dissolved in ethyl acetate (50 ml) andacidified 2M hydrochloric acid (40 ml). The organic phase was separated,washed with water (30 ml) and extracted with 5% potassium carbonatesolution (5×20 ml). The combined basic extracts were then layered withethyl acetate (40 ml) and adjusted to pH1 with 6M hydrochloric acid. Theorganic phase was separated, dried and evaporated to give the titlecompound as a foam (103 mg, 14%): MS (ES−ve) m/z 469 [M−H]⁻; NMR δ(CDCl₃) includes 6.15 (1H, s), 5.38 and 5.18 (1H, 2m), 4.94.7 (2H, m),4.40 (1H, m), 1.52 (3H, s), 1.03 (3H, s), 0.96 (3H, t, J 7 Hz).

Example 1

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (76 mg, 0.55 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid (258 mg, 0.55 mmol) in dry DMF (4 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (56 μl,0.68 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml).

The organic phase was separated, washed with water (2×25 ml) dried andevaporated to a solid. The crude product was purified by flash columnchromatography on silica gel using initially ether and finally ethylacetate as eluant, isolating the title compound isomer A as acrystalline solid (120 mg, 39.5%): mp. 237-238° C.; MS (TSP+ve) m/z 553[MH]⁺; IR ν_(max) (KBr) 1768, 1739, 1671, 1633 cm⁻¹; NMR δ (CDCl₃)includes 7.17 (1H, d, J 10 Hz), 6.42 (1H, bs), 6.38 (1H, d, J 10 Hz),5.49 and 5.39 (1H, 2m), 4.50-4.10 (4H, m), 3.31 (1H, m), 2.36 (2H, q, J7.5 Hz), 1.53 (3H, s), 1.15 (3H, s), 1.13 (3H, t, J 7.5 Hz), 0.99 (3H,d, J 6.25 Hz). (Found: C, 60.72; H, 6.39; S, 5.58. C₂₈H₃₄F₂O₇S requiresC, 60.85; H, 6.30; S, 5.80%) and the title compound isomer B as acrystalline solid (116 mg, 38.2%): mp. 220-222° C.; MS (TSP+ve) m/z 553[MH]⁺; IR ν_(max) (KBr) 1769, 1740, 1678, 1633 cm⁻¹; NMR δ (CDCl₃)includes 7.16 (1H, d, J 10 Hz), 6.43 (1H, bs), 6.38 (1H, d, J 10 Hz),5.49 and 5.39 (1H, 2m), 4.62-4.32 (3H, m), 4.06 (1H, m), 3.32 (1H, m),1.53 (3H, s), 1.12 (6H, m), 0.98 (3H, d, J 6.25 Hz). (Found: C, 60.96;H, 6.28; S, 5.70. C₂₈H₃₄F₂O₇S requires C, 60.85; H, 6.20; S, 5.80%).

Example 2

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl)-ester.

Method 1

Triphenylphosphine (168 mg, 0.64 mmol) was added to a solution ofdiisopropylazodicarboxyiate (0.126 ml, 0.64 mmol) in tetrahydrofuran (3ml) stirred at 0° C. under nitrogen. After formation of a yellowprecipitate a solution of6α,9α-difluoro-11α-hydroxy-16-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid (200 mg, 0.43 mmol) and (R)-α-hydroxy-γ-butyrolactone (65 mg, 0.64mmol) in tetrahydrofuran (3 ml) was added and the progress of thereaction followed by TLC analysis. On completion the solvent was removedand the residue absorbed directly onto silica gel and purified by flashcolumn chromatography, eluting with diethyl ether. The title compoundwas isolated as a white crystalline solid (149 mg, 63%): mp. 236-238°C.; analytical and spectroscopic data were identical to that obtainedpreviously for isomer A of Example 1.

Method 2

Methanesulfonic acid 2-oxo-tetrahydro-furan-3R-yl ester (Intermediate 4,93 mg, 0.52 mmol) was treated with a solution of6α,9β-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid sodium salt (253 mg, 0.52 mmol) in DMF (3 ml) and the mixture wasstirred at 20° C. under nitrogen for 2.5 h. The progress of the reactionwas followed by TLC analysis. On completion the reaction mixture wasdiluted with ethyl acetate and poured into water. The organic solutionwas washed with sodium bicarbonate, 2 M hydrochloric acid, brine, driedand evaporated to dryness to give the title compound (246 mg, 86%): mp.237-238° C.; spectroscopic data were identical to that obtainedpreviously for isomer A of Example 1.

Example 3

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3R-yl) ester.

Triphenylphosphine (168 mg, 0.64 mmol) was added to a solution ofdiisopropylazodicarboxylate (0.126 ml, 0.64 mmol) in tetrahydrofuran (3ml) stirred at 0° C. under nitrogen. After formation of a yellowprecipitate a solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionytoxy-androsta-1,4-diene-17β-carbothioicacid (200 mg, 0.43 mmol) and (S)-α-hydroxy-γ-butyrolactone (65 mg, 0.64mmol) in tetrahydrofuran (3 ml) was added and the progress of thereaction followed by TLC analysis. On completion the solvent was removedand the residue absorbed directly onto silica gel and purified by flashcolumn chromatography, eluting with diethyl ether. The title compoundwas isolated as a white crystalline solid (143 mg, 61%): mp. 219-222°C.; analytical and spectroscopic data were identical to that obtainedpreviously for isomer B of Example 1.

Example 4

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionytoxy-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl ester.

Powdered anhydrous potassium carbonate (102 mg, 0.735 mmol) was added toa stirred solution of6α,9β-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioicacid (Intermediate 3, 346 mg, 0.735 mmol) in dry DMF (5 ml). The mixturewas stirred under nitrogen and then cooled in ice.α-Bromo-γ-butyrolactone (70 μl, 0.85 mmol) was then added and themixture stirred until reaction was complete as monitored by TLC. Thesolution was partitioned between water (25 ml) and ethyl acetate (25ml). The organic phase was separated, washed with water (2×25 ml), driedand evaporated to a solid. The crude product was purified by flashcolumn chromatography on silica gel using initially ether and finallyethyl acetate as eluant, isolating the title compound isomer A as acrystalline solid (85 mg, 20%): mp. 244-246° C.; MS (TSP+ve) m/z 572[MNH₄]⁺; IR ν_(max) (KBr) 1773, 1742 cm⁻¹; NMR δ (CDCl₃) includes 6.14(1H, s), 5.37 and 5.18 (1H, 2m), 4.52 (1H, m), 4.434.28 (2H, m), 4.18(1H, m), 3.33 (1H, m), 2.75 (1H, m), 2.40 (2H, q, J 7 Hz), 1.52 (3H, s),1.13 (3H, t, J 7 Hz), 1.12 (3H, s), 1.01 (3H, d, J 7 Hz) (Found: C,60.33; H, 6.74; S, 5.70, C₂₈H₃₆F₂O₇S requires C, 60.63; H, 6.54; S,5.78%) and the title compound isomer B as a crystalline solid (80 mg,20%): mp. 195-197° C.; MS (TSP+ve) m/z 572 [MNH₄]⁺; IR ν_(max) (KBr)1770, 1747 cm⁻¹; NMR δ (CDCl₃) includes 6.07 (1H, s), 5.30 and 5.11 (1H,2m), 4.49 (1H, m), 4.37-4.24 (2H, m) 3.96 (1H, m), 3.36 (1H, m), 2.64(1H, m), 2.34 (2H, q, J 7 Hz), 1.44 (3H, s), 1.08 (3H, t, J 7 Hz), 1.04(3H, s), 0.93 (3H, d, J 7 Hz) (Found: C, 60.34; H, 6.60; S, 5.63.C₂₈H₃₆F₂O₇S require C, 60.63; H, 6.54; S, 5.78%).

Example 5

17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (59 mg, 0.43 mmol) was added to astirred solution of17α-butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid (206 mg, 0.43 mmol) in dry DMF (3 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (46 μl,0.53 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica geleluting with chloroform-ethyl acetate (2:1), to give the title compoundisomer A as a crystalline solid: (30.7 mg, 13%) mp. 143-145° C.; MS(TSP+ve) m/z 567 [MH]⁺; IR ν_(max) (KBr) 1772, 1741, 1669, 1629 cm⁻¹;NMR δ (CDCl₃) includes 7.14 (1H, d, J 10 Hz), 6.42 (1H, s), 6.39 (1H, d,J 10 Hz), 5.49 and 5.29 (1H, 2m), 4.50 (1H, m), 4.39 (2H, m), 4.31 (1H,m), 4.13 (1H, m), 3.32 (1H, m), 2.75 (1H, m), 1.54 (3H, s), 1.16 (3H,s), 1.00 (3H, d, J 6.25 Hz), 0.95 (3H, t, J 7.25 Hz); (Found: C, 60.87;H, 6.40; S, 5.42. C₂₉H₃₆FO₇S. 0.4 H₂O requires C, 60.70; H, 6.46; S,5.59%) and the title compound isomer B as a crystalline solid (46 mg,19%): mp. 164-166° C.; MS (TSP+ve) m/z 567 [MH]⁺; IR ν_(max) (KBr) 1771,1743, 1668, 1630 cm⁻¹; NMR δ (CDCl₃) includes 7.14 (1H, d, J 10 Hz),6.43 (1H, s), 6.39 (1H, d, J 10 Hz), 5.49 and 5.30 (1H, 2m), 4.55 (1H,m), 4.39 (2H, m), 4.09 (1H, m), 3.31 (1H, m), 2.70 (1H, m), 1.53 (3H,s), 1.14 (3H, s), 0.95 (6H, d, J 6.25 Hz and t, J 7.25 Hz); HRMS (ES+ve)found 567.2200, [MH]⁺. C₂₉H₃₇F₂O₇S requires 567.2205.

Example 6

17α-Acetyloxy-α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (55 mg, 0.40 mmol) was added to astirred solution of17α-acetyloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid (181 mg, 0.40 mmol) in dry DMF (3 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-bromo-γ-butyrolactone (43 μl,0.50 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica geleluting with chloroform:cyclohexane:ethanol (10:10:1), to give the titlecompound isomer A as a crystalline solid (74 mg, 34%): mp. 253-255° C.;MS (TSP+ve) m/z 539 [MH]⁺; IR ν_(max) (KBr) 1766, 1750, 1669, 1631 cm⁻¹;NMR δ (CDCl₃) includes 7.13 (1H, d, J 10 Hz), 6.43 (1H, s), 6.38 (1H, d,J 10 Hz), 5.49 and 5.28 (1H, 2m), 4.50 (1H, m), 4.37 (2H, m), 4.13 (1H,m), 3.30 (1H, m), 2.74 (1H, m), 2.06 (3H, s), 1.54 (3H, s), 1.18 (3H,s), 1.00 (3H, d, J 7 Hz). (Found: C, 58.81; H, 5.88; S, 5.78.C₂₇H₃₂F₂O₇S.0.7 H₂O requires C, 58.83; H, 6.11; S, 5.82%) and the titlecompound isomer B as a crystalline solid (74 mg, 34%): mp. 258-260° C.;MS (TSP+ve) m/z 539 [MH]⁺; IR ν_(max) (KBr) 1772, 1752, 1668, 1630 cm⁻¹;NMR δ (CDCl₃) includes 7.13 (1H, d, J 10 Hz), 6.43 (1H, bs), 6.39 (1H,d, J 10 Hz), 5.49 and 5.29 (1H, 2m), 4.56 (1H, m), 4.40 (2H, m), 4.10(1H, m), 3.70 (1H, m), 3.31 (1H, m), 2.10 (3H, s), 1.55 (3H s), 1.15(3H, s) 1.00 (3H, d, J 7 Hz). (Found: C, 58.76; H, 5.77; S, 5.71.C₂₇H₃₂F₂O₇S 0.7 H₂O requires C, 58.83; H, 6.11; S, 5.82%)

Example 7

9α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (76 mg, 0.55 mmol) was added to astirred solution of9α-fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid (352 mg, 0.75 mmol) in dry DMF (7 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (78 μl,0.94 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by flash column chromatography on silica gel usinginitially ether and finally ethyl acetate as eluant, isolating the titlecompound isomer A as a crystalline solid (124 mg, 30%): MS (TSP+ve) m/z535 [MH]⁺; HRMS (ES+ve) found: 535.2169 [MH]⁺, C₂₉H₃₆FO₇S requires535.2164; IR ν_(max) (nujol) 3443, 1772, 1742, 1716, 1663, 1621, 1605cm⁻¹; NMR δ (CDCl₃) includes 7.22 (1H, d, J 10 Hz), 6.36 (1H, d, J 10Hz), 6.14 (1H, bs), 4.49-4.28 (4H, m), 2.80 (1H, m), 2.37 (2H, q, J 7.5Hz), 1.56 (3H, s), 1.42 (3H, d, J 6.25 Hz), 1.14 (3H, t, J 7.5 Hz), 1.06(3H, s). (Found: C, 61.90; H 6.69; S, 5.83. C₂₈H₃₅FO₇S.0.45 H₂O requiresC, 61.97; H, 6.67; S, 5.91%) and the title compound isomer B as acrystalline solid (156 mg, 37%): MS (TSP+ve) m/z 535 [MH]⁺; HRMS (ES+ve)found: 535.2165 [MH]⁺. C₂₉H₃₆FO₇S requires 535.2164; IR ν_(max) (nujol)3461, 1771, 1743,1707, 1658, 1614 cm⁻¹; NMR δ (CDCl₃) includes 7.22 (1H,d, J 10 Hz), 6.35 (1H, d, J 10 Hz), 6.13 (1H, bs), 4.61 (1H, m), 4.42(1H, m), 4.34 (1H, m), 3.69 (1H, m), 2.82 (1H, m), 2.37 (2H, q, J 7.5Hz), 1.55 (3H, s), 1.38 (3H, d, J 6.25 Hz), 1.15 (3H, t, J 7.5 Hz), 1.01(3H, s). (Found: C, 61.51; H, 6.72; S, 5.61. C₂₈H₃₅FO₇S.0.6 H₂O requiresC, 61.34; H, 6.71; S, 5.85%).

Example 8

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-11β-carbothioicacid S-(5-oxo-tetrahydro-furan-2-yl) ester.

Powdered anhydrous potassium carbonate (76 mg, 0.55 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid (258 mg, 0.55 mmol) in dry DMF (5 ml). The mixture was stirredunder nitrogen and then cooled in ice. γ-Chloro-γ-butyrolactone (69 μl,0.69 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica gel,eluting with chloroform-cyclohexane-ethanol (20:20:1), to give the titlecompound isomer A as a crystalline solid (50 mg, 16%): mp. 152° C.; MS(TSP+ve) m/z 553 [MH]⁺; IR ν_(max) (KBr) 3459, 1791, 1742, 1704, 1667,1631 cm⁻¹; NMR δ (DMSO d₆) includes 7.13 (1H, d, J 10 Hz), 6.44 (1H, s),6.39 (1H, d, J 10 Hz), 6.28 (1H, m), 5.48 and 5.28 (1H, 2m), 4.41 (1H,m), 3.41 (1H, m), 2.38 (2H, q, J 7 Hz), 1.52 (3H, s), 1.14 (3H, t, J 7Hz), 1.14 (3H, s), 1.01 (3H, d, J 7 Hz); HRMS (ES+ve) found: 553.6446[MH]⁺, C₂₈H₃₅F₂O₇S requires 553.6445, and the title compound isomer B asa crystalline solid (34 mg, 10%): mp. 210-213° C.; MS (TSP+ve) m/z 553[MH]⁺; IR ν_(max) (KBr) 1787, 1743, 1669, 1632 cm⁻¹; NMR δ (CDCl₃)includes 7.13 (1H, d, J 10 Hz), 6.44 (1H, d, J 10 Hz), 6.38 (1H, s),6.24 (1H, m) 5.48 and 5.28 (1H, 2m), 4.40 (1H, m), 3.32 (1H, m), 2.36(2H, q, J 7 Hz), 1.52 (3H, s), 1.16 (3H, m), 1.12 (3H, t, J 7 Hz), 1.02(3H, d, J 7 Hz); HRMS (ES+ve) found 553.6445 [MH]⁺, C₂₈H₃₅F₂O₇S requires553.6445.

Example 9

6α,9α-Difluoro-11α-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-4-yl) ester.

Powdered anhydrous potassium carbonate (69 mg, 0.5 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid (234 mg, 0.5 mmol) in dry DMF (2.5 ml). The mixture was stirredunder nitrogen and then cooled in ice. 2(5H)-Furanone (400 μl, 5.63mmol) was then added and the mixture stirred until reaction was completeas monitored by TLC. The solution was partitioned between water (25 ml)and ethyl acetate (25 ml). The organic phase was separated, washed withwater (2×25 ml) dried and evaporated to a solid. The crude product waspurified by preparative layer chromatography on silica gel using ethylacetate as eluant, isolating the title compound as a crystalline solid(9 mg, 3%): MS (FAB+ve) m/z 553 [MH]⁺; IR ν_(max) (KBr) 3474, 1784,1745, 1667, 1633 cm⁻¹; NMR δ (CDCl₃) includes 7.13 (1H, d, J 10 Hz),6.45 (1H, s), 6.38 (1H, d, J 10 Hz), 5.48 and 5.28 (1H, 2m), 4.80-4.67(1H, m), 4.41 (1H, m), 4.35-4.2 (2H, m), 3.29 (1H, m), 3.05 (0.5H, dd, J9 and 4 Hz), 2.98 (0.5H, dd, J 9 and 4 Hz), 2.59 (0.5H, t, J 5 Hz), 2.52(0.5H, t, J 5 Hz), 2.47 (3H, q, J 8 Hz), 1.54 (3H, s), 1.05-1.27 (6H,m), 0.97 and 0.98 (3H, 2d, J 8 Hz); HRMS (ES+ve) found: 553.2083 [MH]⁺,C₂₈H₃₅F₂O₇S requires 553.2072;

Example 10

6α,9α-Difluoro-11α-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxyiicacid (2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (103 mg, 0.75 mmol) was added toa stirred solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (340 mg, 0.75 mmol) in dry DMF (7 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (78 μl,0.94 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml) dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica gel,eluting with chloroform-cyclohexane-ethanol (20:20:1), to give the titlecompound isomer A as a crystalline solid (43 mg, 11%): mp. 205-206° C.;MS (TSP+ve) m/z 537 [MH]⁺; IR ν_(max) (KBr) 3443, 1786, 1747, 1669,1632, 1612 cm⁻¹; NMR δ (CDCl₃) includes 7.27 (1H, d, J 10 Hz), 6.29 (1H,d, J 10 Hz), 6.11 (1H, s), 5.68 (1H, m), 5.70 and 5.55 (1H, 2m),4.33-4.22 (2H, m), 4.16 (1H, m), 3.21 (1H, m), 2.35 (2H, q, J 7 Hz),1.48 (3H, s), 1.04 (3H, s), 1.00 (3H, t, J 7 Hz), 0.86 (3H, d, J 7 Hz);HRMS (ES+ve) found: 537.2295 [MH]⁺, C₂₈H₃₅F₂O₈ requires 537.2294, andthe title compound isomer B as a crystalline solid (43 mg, 11%): mp.231-233° C.; MS (TSP+ve) m/z 537 [MH]⁺; IR ν_(max) (KBr) 3482, 1789,1747, 1668, 1630 cm⁻¹; NMR δ (CDCl₃) includes 7.13 (1H, d, J 10 Hz),6.41(1H, s), 6.39 (1H, d, J 10 Hz), 5.51 and 5.20 (1H, 2m), 5.10 (1H,m), 4.58 (1H, m), 4.46-4.32 (2H, m), 3.30 (1H, m), 2.40 (2H, q, J 7 Hz),1.72 (3H, s), 1.55 (3H, s), 1.00 (3H, t, J 7 Hz), 0.96 (3H, d, J 7 Hz);HRMS (ES+ve) found: 537.2299 [MH]⁺, C₂₈H₃₅F₂O₈ requires 537.2297.

Example 11

6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (2-oxo-Aetrahydro-furan-5-yl) ester.

Powdered anhydrous potassium carbonate (76 mg, 0.55 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (249 mg, 0.55 mmol) in dry DMF (5 ml). The mixture was stirredunder nitrogen and then cooled in ice. γ-Chloro-γ-butyrolactone (83 μl,0.69 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica gel,eluting with chloroform-cyclohexane-ethanol (20:20:1), to give the titlecompound isomer A as a crystalline solid (62 mg, 21%): mp. 263-266° C.;MS (TSP+ve) m/z 537 [MH]⁺; HRMS (ES+ve) found: 537.5780 [MH]⁺,C₂₈H₃₅F₂O₈ requires 537.5779; IR ν_(max) (KBr) 3459, 1789, 1733, 1669,1633 cm⁻¹; NMR δ (DMSO d₆) includes 7.10 (1H, d, J 10 Hz), 6.69 (1H, m),6.44 (1H, s), 6.38 (1H, d, J 10 Hz), 5.48 and 5.28 (1H, 2m), 4.37 (1H,m), 3.33 (1H, m), 2.37 (2H, q, J 7 Hz), 1.53 (3H, s), 1.13 (3H, t, J 7Hz), 1.08 (3H, s), 0.93 (3H, d, J 7 Hz). (Found: C, 61.77; H, 6.15.C₂₈H₃₄F₂O₇ 0.3 H₂O requires C, 62.05; H, 6.43%) and the title compoundisomer B as a crystalline solid (48 mg, 16%): mp. 241-243° C.; MS(TSP+ve) m/z 537 [MH]⁺; HRMS (ES+ve) found: 537.5788 [MH]⁺, C₂₈H₃₅F₂O₈requires 537.5779; IR ν_(max) (KBr) 3480, 1789, 1747, 1668, 1628 cm⁻¹;NMR δ (DMSO d₆) includes 7.12 (1H, d, J 10 Hz), 6.58 (1H, m), 6.43 (1H,s), 6.38 (1H, d, J 10 Hz), 5.48 and 5.28 (1H, 2m), 4.39 (1H, m), 3.22(1H, m), 2.36 (2H, q, J 7 Hz), 1.53 (3H, s), 1.11 (3H, t, J 7 Hz), 1.10(3H, s), 0.95 (3H, d, J 7 Hz). (Found: C, 61.69; H, 6.05. C₂₈H₃₄F₂O₈ 0.4H₂O requires C, 61.85; H, 6.45%).

Example 12

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (44 mg, 0.32 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (130 mg, 0.286 mmol) in dry DMF (1.4 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (30 μl,0.36 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative normal phase HPLC (Dynamax 60 Å C18,25 cm×41 mm i.d.) eluting with 70-90% ethyl acetate/heptane at 45 ml/minwith detection at 270 nm to give the title compound isomer A as acrystalline solid (29 mg, 20%): mp. 308-312° C.; MS (TSP+ve) m/z 539[MH]⁺; IR ν_(max) (KBr) 3310, 1778, 1694, 1668, 1629 cm⁻¹; NMR δ (DMSOd₆) includes 7.24 (1H, d, J 10 Hz), 6.30 (1H, d, J 10 Hz), 6.12 (1H, s),5.73 and 5.52 (1H, 2m), 5.58 (1H, bs), 4.88 (1H, m), 4.47-4.15 (4H, m),1.49 (3H, s), 1.37 (3H, s), 1.20 (3H, s), 0.90 (3H, s). (Found: C,59.77; H, 6.01. C₂₇H₃₂F₂O₇S. 0.3 H₂O requires C, 59.61; H, 6.04%) andthe title compound isomer B as a crystalline solid (43 mg, 29%): mp.275-278° C.; MS (TSP+ve) m/z 539 [MH]⁺; IR ν_(max) (KBr) 3415, 2928,1779, 1669, 1633 cm⁻¹ ; NMR δ (DMSO d₆) includes 7.25 (1H, d, J 10 Hz),6.30 (1H. d, J 10 Hz), 6.11 (1H, s), 5.73 and 5.54 (1H, 2m), 5.57 (1H,m), 4.89 (1H, m), 4.48-4.16 4H, m), 1.50 (3H, s), 1.35 (3H, s), 1.20(3H, s), 0.88 (3H, s). (Found: C, 59.35; H, 6.05. C₂₇H₃₂F₂O₇S. 0.4 H₂Orequires C, 59.42; H, 6.06%).

Example 13

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-5-yl) ester.

Powdered anhydrous potassium carbonate (61 mg, 0.44 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (200 mg, 0.44 mmol) in dry DMF (5 ml). The mixture was stirredunder nitrogen and then cooled in ice. γ-Chloro-γ-butyrolactone (64 mg,0.53 mmol) in dry DMF (1 ml) was then added and the mixture stirreduntil reaction was complete as monitored by TLC. The solution waspartitioned between water (25 ml) and ethyl acetate (25 ml). The organicphase was separated, washed with water (2×25 ml), dried and evaporatedto a solid. The crude product was purified by flash columnchromatography on silica gel, eluting with cyclohexane-ethyl acetate(1:1) to give the title compound isomer-A as a crystalline solid (67 mg,28%): mp. 304-307° C.; MS (TSP+ve) m/z 539 [MH]⁺; IR ν_(max) (KBr) 1784,1697, 1668, 1630 cm⁻¹; NMR δ (CDCl₃) includes 7.14 (1H, d, J 10 Hz),6.42 (1H, s), 6.39 (1H, d, J 10 Hz), 6.31 (1H, m), 5.50 and 5.30 (1H,2m), 5.00 (1H, m), 4.42 (1H, m), 1.65 (3H, s), 1.49 (3H, s), 1.37 (3H,s), 1.00 (3H, s). (Found: C, 59.76; H, 6.13; S, 5.80. C₂₇H₃₂F₂O₇S.0.2H₂O requires C, 59.81; H, 6.02; S, 5.91%) and the title compound isomerB as a crystalline solid (67 mg, 28%): mp. 270-273° C.; MS (TSP+ve) m/z539 [MH]⁺; IR ν_(max) (KBr) 1792, 1700, 1666, 1629 cm⁻¹; NMR δ (DMSO d₆)includes 7.26 (1H, d, J 10 Hz), 6.31 (1H, d, J 10 Hz), 6.15(2H, m), 5.74and 5.54 (1H, 2m), 5.56 (1H, s), 4.93 (1H, m), 4.20 (1H, m), 1.50 (3H,s), 1.35 (3H, s), 1.14 (3H, s), 0.90 (3H, s). (Found: C, 59.16; H, 6.01;S, 5.54. C₂₇H₃₂F₂O₇S.0.5 H₂O requires C, 59.22; H, 6.07; S, 5.86%).

Example 14

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

To a stirred suspension of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androst-4-ene-17β-carbothioicacid (448 mg, 1.02 mmol) in dichloromethane (8 ml) was addedtriethylamine (160 μl, 1.15 mmol) followed by diethylchlorophosphate(160 μl, 1.11 mmol) and the mixture stirred to allow formation of theintermediate mixed anhydride. A solution of the sodium salt ofα-mercapto-γ-butyrolactone [made by addition of sodium hydride (70 mg of60% oil dispersion, 1.75 mmol) to a solution ofα-mercapto-γ-butyrolactone (170 mg, 1.44 mmol) in DMF (4 ml)] was addedand the reaction followed by TLC analysis. On completion the reactionwas diluted with ethyl acetate (50 ml) and washed with 1M HCl (2×50 ml),water (50 ml), saturated sodium bicarbonate solution (2×50 ml), water(50 ml) and saturated brine solution (50 ml). The organic layer was thendried and concentrated to yield the crude material as a gum. This waspurified by flash column chromatography on silica gel, eluting withethyl acetate-cyclohexane (1:1). The title compound isomer A wasisolated as a crystalline solid (60 mg, 11%): mp. 169-173° C.; MS(TSP+ve) m/z 541 [MH]⁺; IR ν_(max) (KBr) 3397, 2959, 1780, 1690, 1657cm⁻¹; NMR δ (CDCl₃) includes 6.17 (1H, s), 5.36 and 5.24 (1H, 2m), 5.05(1H, d, J 5 Hz), 4.49 (1H, t, J 4 Hz), 4.44-4.34 (3H, m), 1.55 (3H, s),1.51 (3H, s), 1.29 (3H, s), 1.03 (3H, s). (Found: C, 58.92; H, 6.03; S,6.25. C₂₇H₃₄F₂O₇S 0.4 H₂O requires C, 59.20; H, 6.40; S, 5.85%) and thetitle compound isomer B isolated as a foam (79 mg, 14%): MS (TSP+ve) m/z541 [MH]⁺; IR ν_(max) (KBr) 3379, 1780, 1691, 1658 cm⁻¹; NMR δ (CDCl₃)includes 6.17 (1H, s), 5.36 and 5.24 (1H, 2m), 5.02 (1H, d, J 5 Hz) 4.59(1H, t, J 4.5 Hz), 4.46-4.25 (2H, m), 3.98 (1H, t, J 10 Hz), 1 54 (3H,s), 1.51 (3H, s), 1.32 (3H, s), 0.98 (3H, s). (Found: C, 59.32; H 6.43;S, 5.96. C₂₇H₃₄F₂O₇S.0.3 H₂O requires C, 59.39; H, 6.39; S, 5.87%).

Example 15

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3S-yl) amide

A mixture of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (100 mg, 0.228 mmol), (S)-α-amino-γ-butyrolactone hydrochloride (46mg, 0.202 mmol), 1-hydroxy-benzotriazole (31 mg, 0.228 mmol),O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(81 mg, 0.251 mmol) and diisopropylethylamine (0.04 ml, 0.228 mmol) inDMF (5 ml) was stirred and heated at 100° C. under an atmosphere ofnitrogen until the reaction was complete, as monitered by TLC analysis.After cooling to room temperature ethyl acetate (20 ml) and hydrochloricacid (2M, 15 ml) were added. The aqueous layer was separated andextracted with ethyl acetate (20 ml). The combined organic layers werewashed with water (15 ml) and saturated brine solution (15 ml), driedover anhydrous MgSO₄ and concentrated to yield the crude product as agum. This was purified by flash column chromatography on silica gel,eluting with ethyl acetate, to yield the title compound as a crystallinesolid (60 mg, 57%): mp. 181-184° C.; MS (TSP+ve) 522 [MH]⁺; IR ν_(max)(KBr) 3320, 1774, 1669, 1633 cm⁻¹; NMR δ (CDCl₃) includes 7.18 (1H, d, J10 Hz), 6.93 (1H, bs), 6.42 (1H, s), 6.38 (1H, d, J 10 Hz), 5.50 and5.30 (1H, 2m), 5.08 (1H, bs), 4.91 (1H, m), 4.51 (1H, m), 4.33 (2H, m),2.72 (1H, m), 1.79 (3H, s), 1.35 (3H, s), 1.22 (3H, s), 1.04 (3H, s).(Found: C, 60.63; H, 6.59; N, 2.44. C₂₇H₃₃F₂NO₇.0.7 H₂O requires C,60.71; H, 6.49; N, 2.62%).

Example 16

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide

A mixture of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (259 mg, 0.591 mmol), (±)-α-amino-γ-butyrolactone hydrochloride(108 mg, 0.591 mmol), 1-hydroxy-benzotriazole (80 mg, 0.591 mmol),1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (113 mg,0.591 mmol) and diisopropylethylamine (0.11 ml, 0.650 mmol) indimethylformamide (20 ml) was stirred and heated at 100° C. under anatmosphere of nitrogen until the reaction was complete, as monitered byTLC analysis. After cooling to room temperature ethyl acetate (20 ml)and hydrochloric acid (2M, 5 ml) were added. The aqueous layer wasseparated and extracted with ethyl acetate (20 ml). The combined organiclayers were washed with water (15 ml) and saturated brine solution (15ml), dried over anhydrous MgSO₄ and concentrated to yield the crudeproduct as a gum. This was purified by preparative layer chromatographyon silica gel, eluting with 5:2 ethyl acetate:cyclohexane, to yield thetitle compound S-isomer, isomer A, as a crystalline solid as obtainedabove and the title compound R-isomer, isomer B, as a crystalline solid(40 mg, 13%). mp. 333-336° C.; MS (TSP+ve) 522 [MH]⁺; IR ν_(max) (KBr)3484, 1775, 1668, 1632 cm⁻¹; NMR δ (DMSO d₆) includes 8.32 (1H, s), 7.24(1H, d, J 10 Hz), 6.30 (1H, d, J 10 Hz), 6.10 (1H, s), 5.72 and 5.52(1H, 2m), 5.52 (1H, bs), 4.95 (1H, m), 4.57 (1H, m), 4.34 (1H, m), 4.20(1H, m), 2.00 (3H, s), 1.34, (3H, s) 1.17 (3H, s), 0.91 (3H, s). (Found:C, 62.51; H, 6.61; N, 2.33%, C₂₇H₃₃F₂NO₇ requires C, 62.18; H, 6.38; N,2.69%).

Example 17

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (65 mg, 0.47 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (205 mg, 0.47 mmol) in dry DMF (4 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (50 μl,0.58 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml) dried and evaporated to a solid. The crudeproduct was purified by preparative layer chromatography on silica gel,eluting with chloroform-cyclohexane-ethanol (10:10:1), to give the titlecompound isomer A as a crystalline solid (65 mg, 27%): mp. 253-255° C.;MS (TSP+ve) m/z 523 [MH]⁺; IR ν_(max) (KBr) 1785, 1732, 1667, 1631 cm⁻¹;NMR δ (DMSO d₆) includes 7.20 (1H, d, J 10 Hz), 6.44 (1H, s), 6.39 (1H,d, J 10 Hz), 5.68 (1H, m), 5.49 and 5.30 (1H, 2m), 5.18(1H, m), 4.52(1H, m), 4.37(2H, m), 2.71 (1H, m), 1.52 (3H, s), 1.42 (3H, s), 1.21(3H, s), 1.08 (3H, s). (Found: C, 61.43; H, 6.07. C₂₇H₃₂F₂O₈ 0.3 H₂Orequires C, 61.43; H, 6.22%) and the title compound isomer B as acrystalline solid (53.2 mg, 22%): mp. 300-304° C.; MS (TSP+ve) m/z 523[MH]⁺: IR ν_(max) (KBr) 1793, 1743, 1666, 1632 cm⁻¹; NMR δ (DMSO d₆)includes 7.10 (1H, d, J 10 Hz), 6.44 (1H, s), 6.39 (1H, d, J 10 Hz),5.49 and 5.30 (1H, 2m), 5.38 (1H, m), 5.15 (1H, m), 4.46 (1H, m), 4.39(2H, m), 2.70 (1H, m), 1.52 (3H, s), 1.42 (3H, s), 1.25 (3H, s), 1.06(3H, s). (Found: C, 61.76; H, 6.11. C₂₈H₃₂F₂O₈ requires C, 62.06; H,6.17%).

Example 18

6α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-turan-3-yl) ester.

Powdered anhydrous potassium carbonate (24 mg, 0.175 mmol) was added toa stirred solution of16α,17α-butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (69 mg, 0.16 mmol) in dry DMF (1.5 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (16.5 μl,0.20 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative normal phase HPLC (Dynamax 60 Å C18,25 cm×41 mm i.d.) eluting with 70-90% ethyl acetate/heptane at 45 ml/minwith detection at 270 nm and the title compound diastereomeric mixture Aisolated as a crystalline solid (23 mg, 28%): mp. 129-132° C.; MS(TSP+ve) m/z 517 [MH]⁺; IR vrax (KBr) 3459, 1775, 1693, 1653, 1618 cm⁻¹;NMR δ (DMSO d₆) includes 7.30 (1H, d, J 10 Hz), 6.18 (1H, d, J 10 Hz),5.91 (1H, s), 4.87 (1H, m), 4.65 (2H, m), 4.30 (4H, m), 1.38 (3H, s),0.97 (6H, m). (Found: C, 64.34; H, 7.24; S, 5.39. C₂₈H₃₆O₇S 0.5 H₂Orequires C, 64.26; H, 7.19; S, 5.72%) and the title compounddiastereomeric mixture B as a crystalline solid (29 mg, 35%) mp.149-154° C.; MS (TSP+ve) m/z 539 [MH]⁺; IR ν_(max) (KBr) 3468, 1775,1688, 1654, 1617 cm⁻¹; NMR δ (DMSO d₆) includes 7.30 (1H, d, J 10 Hz),6.16 (1H, d, J 10 Hz), 5.90 (1H, s), 4.86 (1H, m), 4.68 (2H, m), 4.30(4H, m), 1.37 (3H, s), 0.90 (6H, m) (Found: C, 64.43; H, 7.12; S, 5.78.C₂₈H₃₆O₇S.0.3 H₂O requires C, 64.42; H, 7.07; S, 6.14%).

Example 19

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

To a stirred suspension of16α,17α-(R-butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid (200 mg, 0.44 mmol) in dichloromethane (3 ml) was addedtriethylamine (61 μl, 0.44 mmol) followed by diethylchlorophosphate (64μl, 0.44 mmol) and the mixture stirred to allow formation of theintermediate mixed anhydride. A solution of the sodium salt ofα-mercapto-γ-butyrolactone [made by addition of sodium hydride (24 mg of60% oil dispersion, 0.6 mmol) to a solution ofα-mercapto-γ-butyrolactone (72 mg, 0.6 mmol) in DMF (1.5 ml)] was addedand the reaction followed by TLC analysis. On completion the reactionwas diluted with ethyl acetate (50 ml) and washed with 1M hydrochloricacid (2×50 ml), water (50 ml), saturated sodium bicarbonate solution(2×50 ml), water (50 ml) and saturated brine solution (50 ml). Theorganic layer was then dried and concentrated to yield the crudematerial as a gum. This was purified by preparative layer chromatographyon silica gel, eluting ethyl acetate-40-60 petroleum ether (1:1). Thetitle compound isomer A was isolated as a foam after trituration withdiethyl ether (84.5 mg, 35%): MS (TSP+ve) m/z 555 [MH]⁺; IR ν_(max)(KBr) 3480, 1777 cm⁻¹; NMR δ (CDCl₃) includes 6.15 (1H, s), 5.37 and5.18 (1H, 2m), 4.85 (1H, d, J 5 Hz), 4.74 (1H, t, J 4 Hz), 4.40 (1H, m),4.54-4.22 (3H, m), 1.53 (3H, s), 1.02 (3H, s), 0.96 (3H, t, J 7.5 Hz).Found: C, 60.91; H, 7.05; S, 5.48. C₂₈H₃₆F₂O₇S 0.55 Et₂O requires C,60.92; H, 7.03; S, 5.39%) and the title compound isomer B isolated as afoam (68 mg, 31%): MS (TSP+ve) m/z 555 [MH]⁺; IR ν_(max) (KBr) 3466,1771 cm⁻¹; NMR δ (CDCl₃) includes 6.14 (1H, s), 5.36 and 5.18 (1H, 2m),4.82 (1H, d, J 5 Hz), 4.77 (1H, t, J 4.5 Hz), 4.35 (4H, m), 1.52 (3H,s), 0.96 (6H, t, s, J 7.5 Hz). (Found: C, 61.22; H, 7.06; S, 5.39.C₂₈H₃₆F₂O₇S 0.2 C₅H₁₂ requires C, 61.37; H, 6.68; S, 5.59%).

Example 20

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester.

To a suspension of sand (10 g) in heptane (12.5 ml) at room temperaturewas added6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester (Example 12, 0.5 g, 0.93mmol) with vigorous stirring. To this suspension was added butanal(0.123 ml, 1.39 mmol) followed by perchloric acid (0.320 ml, 3.71 mmol)and the suspension stirred at room temperature until reaction wascomplete as evidenced by TLC analysis. The reaction was cooled in icebefore addition of 10% aq. K₂CO₃ solution (8 ml), ensuring the internaltemperature did not rise above 25° C. The sand was collected byfiltration and washed with heptane (4×20 ml), water (6×20 ml) then ethylacetate (4×40 ml) and the combined ethyl acetate layers washed withbrine solution (20 ml) and dried before concentrating to yield the crudeproduct as a solid. The material was purified by flash columnchromatography on silica gel, eluting with ethyl acetate-cyclohexane(3:2). The title compound isomer A was isolated as a crystalline solid(74 mg, 15%): mp. 260-264° C.; MS (TSP+ve) m/z 553 [MH]⁻¹; IR ν_(max)(KBr) 3341, 1774, 1698, 1668, 1629 cm⁻¹; NMR δ (DMSO d₆) includes 7.25(1H, d, J 10 Hz), 6.30 (1H, d, J 10 Hz), 6.10 (1H, bs), 5.70 and 5.55(1H, 2m), 5.60 (1H, bs), 4.70 (2H, m), 4.50-4.15 (4H, m), 1.48 (3H, s),0.95 (3H, s), 0.86 (3H, t, J 7 Hz). (Found: C, 60.72; H, 6.01; S, 5.51.C₂₈H₃₄F₂O₇S requires C, 60.86; H, 6.20; S, 5.80%) and the title compoundisomer B, also as a crystalline solid (53 mg, 10%): mp. 254-257° C.; MS(TSP+ve) m/z 553 [MH]⁺; IR ν_(max) (KBr) 3376, 1776, 1693, 1667, 1623cm⁻¹; NMR δ (DMSO d₆) includes 7.25 (1H, d, J 10 Hz), 6.25 (1H, d, J 10Hz), 6.10 (1H, bs), 5.70 and 5.55 (1H, 2m), 5.60 (1H, bs), 4.70 (1H, m),4.50-4.15 (4H, m), 1.47 (3H, s), 0.86 (6H, m). (Found: C, 60.91; H,6.09; S, 5.62. C₂₈H₃₄F₂O₇S requires C, 60.86; H, 6.20; S, 5.80%).

Example 21

16α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-andrqrta-1,4-diene-17-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester.

Powdered anhydrous potassium carbonate (37 mg, 0.264 mmol) was added toa stirred solution of16α,17α-butylidenedioxy-6α,9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carboxyiicacid (100 mg, 0.24 mmol) in dry DMF (1.3 ml). The mixture was stirredunder nitrogen and then cooled in ice. α-Bromo-γ-butyrolactone (25 μl,0.30 mmol) was then added and the mixture stirred until reaction wascomplete as monitored by TLC. The solution was partitioned between water(25 ml) and ethyl acetate (25 ml). The organic phase was separated,washed with water (2×25 ml), dried and evaporated to a solid. The crudeproduct was purified by preparative reversed phase HPLC (Dynamax 60 ÅC18, 25 cm×41 mm i.d.) eluting with 70-90% MeCN/H₂O at 45 ml/min withdetection at 230 nm and the title compound diastereomeric mixture Aisolated as a crystalline solid (41 mg, 34%): mp. 177-180° C.; MS(TSP+ve) m/z 501 [MH]⁺; IR ν_(max) (KBr) 3515, 1789, 1738, 1653, 1616cm⁻¹; NMR δ (DMSO d₆) includes 7.30 (1H, d, J 10 Hz), 6.18 (1H, d, J 10Hz), 5.91 (1H, s), 5.65 (1H, m), 5.18 (1H, m), 4.86 (2H, m), 4.38 (3H,m), 1.38 (3H, s), 0.93 (3H, s), 0.85 (3H, t, J 7 Hz). (Found: C, 66.31;H, 7.30. C₂₈H₃₆O₈. 0.4 H₂O requires C, 66.23; H, 7.30%) and the tilecompound diastereomeric mixture B as a crystalline solid (38 mg, 31%):mp. 128-133° C.; MS (TSP+ve) m/z 501 [MH]⁺; IR ν_(max) (KBr) 3490, 1789,1738, 1653, 1614 cm⁻¹; NMR δ (DMSO d₆) includes 7.30 (1H, d, J 10 Hz),6.17 (1H, d, J 10 Hz), 5.92 (1H, s), 5.60 (1H, m), 4.77 (3H, m), 4.32(3H, m), 1.38 (3H, s), 0.95 (3H, s), 0.84 (3H, t, J 7 Hz). (Found: C,65.73; H, 7.23. C₂₈H₃₆O₈.0.6 H₂O requires C, 65.76; H, 7.33%).

Example 22

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide

A mixture of16α,17α-(R-butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid (0.98 g, 2.16 mmol), (±)-α-amino-γ-butyrolactone hydrobromide (393mg, 2.16 mmol), 1-hydroxy-benzotriazole (292 mg, 2.16 mmol),O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(692 mg, 2.16 mmol) and diisopropylethylamine (1.13 ml, 6.48 mmol) inDMF (25 ml) was stirred and heated at 100° C. under an atmosphere ofnitrogen until the reaction was complete, as monitored by TLC analysis.After cooling to room temperature ethyl acetate (100 ml) and 2Mhydrochloric acid (100 ml) were added. The organic layer was separatedand extracted successively with water (100 ml), 1M aqueous sodiumhydroxide solution (100 ml), water (100 ml) and saturated brine solution(100 ml). The organic layer was dried over anhydrous MgSO₄ andconcentrated to yield the crude product as a gum. This was purified byflash column chromatography on silica gel, eluting with ethylacetate:cyclohexane (1:1) followed by ethyl acetate, to yield twofractions. These were further purified by reverse phase preparative HPLC(Dynamax 60A C18, 25 cm×41 mm i.d.) eluting with 47% MeCN/H₂O at 45mlmin with detection at 230 nm, in both cases. The less polar fractionafforded the title compound isomer A as a white solid (30 mg, 3%): mp.165° C.; MS (TSP+ve) 538 [MH]⁻; IR ν_(max) (KBr) 3468, 3407,3351,1778,1663, 1520 cm⁻¹; NMR δ (CDCl₃) includes 6.72 (1H, d, J 8 Hz),6.14 (1H, s), 5.38 and 5.18 (1H, 2m), 4.98 (1H, d, J 5 Hz), 4.82 (1H,m), 4.67 (1H, t, J 4 Hz), 4.50 (1H, t, J 9 Hz), 4.37 (2H, m), 1.05 (3H,s), 0.95 (3H, t, J 7 Hz). (Found: C, 63.00; H, 6.75; N, 2.13.C₂₈H₃₇F₂NO₇ requires C, 62.51; H, 6.88; N, 2.60%). The more polarfraction was further purified by preparative TLC, eluting several timeswith ethyl acetate:cyclohexane (3:1), to afford the title compoundisomer B as a white solid (25 mg, 2%): mp. 155-160° C.; MS (TSP+ve) 538[MH]⁺; IR ν_(max) (KBr) 3382, 1779, 1668, 1516 cm⁻¹; NMR δ (CDCl₃)includes 6.98 (1H, d, J 6 Hz), 6.13 (1H, s), 5.37 and 5.18 (1H, 2m),4.94 (1H, d, J 5 Hz), 4.54 (1H, t, J 4 Hz), 4.53 (1H, t, J 9 Hz),4.484.24 (3H, m), 1.02 (3H, s), 0.94 (3H, t, J 7 Hz). (Found: C, 60.94;H, 7.15; N, 2.21. C₂₈H₃₇F₂NO₇ 0.8 H₂O requires C, 60.92; H, 7.05; N,2.54%).

Example 23

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-4S-yl) amide

A mixture of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (0.5 g, 1.14 mmol), 4S-amino-γ-butyrolactone hydrobromide (207 mg,1.14 mmol), 1-hydroxy-benzotriazole (154 mg, 1.14 mmol),O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(365 mg, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.44 mmol) in DMF(15 ml) was stirred and heated at 100° C. under an atmosphere ofnitrogen until the reaction was complete, as monitored by TLC analysis.After cooling to room temperature ethyl acetate (100 ml) and 2Mhydrochloric acid (100 ml) were added. The organic layer was separatedand extracted successively with 1M aqueous sodium hydroxide solution(100 ml) and saturated brine solution (100 ml). The organic layer wasdried over anhydrous MgSO₄ and concentrated to yield the crude productas a gum. This was purified by reverse phase preparative HPLC (Dynamax60A C18, 25 cm×41 mm i.d.) eluting with 40% MeCN/H₂O at 45 ml/min withdetection at 230 nm affording the title compound as a white solid (129mg, 22%): mp. 204-206° C.; MS (TSP+ve) 522 [MH]⁺; IR ν_(max) (KBr) 3325,1778, 1667,1631, 1527 cm⁻¹; NMR δ (DMSO d₆) includes 8.44 (1H, d, J 6Hz), 7.26 (1H, d, J 10 Hz), 6.30 (1H, d, J 10 Hz), 6.11 (1H, s), 5.74and 5.55 (1H, 2m), 5.46 (1H, s), 4.95 (1H, d, J 2 Hz), 4.57 (1H, m),4.48 (1H, dd, J 8 and 8 Hz), 4.17 (1H, bd), 4.08 (1H, dd, J 9 and 2 Hz),2.83 (1H, dd, J 17 and 8 Hz), 1.51 (3H, s), 1.34 (3H, s), 1.12 (3H, s),0.88 (3H, s). (Found: C, 61.17; H, 6.55; N, 3.35. C₂₇H₃₃F₂NO₇.0.3 CH₃CN.0.4 H₂O requires C, 61.27; H, 6.46; N, 3.37%).

Example 24

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-4R-yl) amide

A mixture of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (0.5 g, 1.14 mmol), 4R-amino-γ-butyroiactone hydrobromide (207 mg,1.14 mmol), 1-hydroxy-benzotriazole (154 mg, 1.14 mmol),O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(365 mg, 1.14 mmol) and diisopropylethylamine (0.6 ml, 3.44 mmol) in DMF(15 ml) was stirred and heated at 100° C. under an atmosphere ofnitrogen until the reaction was complete, as monitored by TLC analysis.After cooling to room temperature ethyl acetate (100 ml) and 2Mhydrochloric acid (100 ml) were added. The organic layer was separatedand extracted successively with 1M aqueous sodium hydroxide solution(100 ml) and saturated brine solution (100 ml). The organic layer wasdried over anhydrous MgSO₄ and concentrated to yield the crude productas a gum. This was purified by flash column chromatography on silicagel, eluting with ethyl acetate:cyclohexane (4:1) and was furtherpurified by reverse phase preparative HPLC (Dynamax 60A C18, 25 cm×41 mmi.d.) eluting with 40% MeCN/H₂O at 45 ml/min with detection at 230 nmaffording the title compound as a white solid (99 mg, 17%): mp. 322° C.;MS (TSP+ve) 522 [MH]⁺; IR ν_(max) (KBr) 3360, 1780, 1768, 1666, 1627,1534 cm⁻¹; NMR δ (DMSO d₆) includes 8.50 (1H, d, J 7 Hz), 7.26 (1H, d, J10 Hz), 6.30 (1H, dd, J 10 and 1 Hz), 6.11 (1H, s), 5.73 and 5.54 (1H,2m), 5.43 (1H, bd, J 1 Hz), 4.95 (1H, d, J 4 Hz), 4.58 (1H, m), 4.43(1H, dd, J 8 and 8 Hz), 4.37 (1H, bd), 4.03 (1H, dd, J 9 and 4 Hz), 2.83(1H, dd, J 18 and 9 Hz), 1.50 (3H, s), 1.34 (3H, s), 1.13 (3H, s), 0.88(3H, s). (Found: C, 61.46; H, 6.48; N, 2.76. C₂₇H₃₃F₂NO₇.0.3 H₂Orequires C, 61.54; H, 6.43; N, 2.66%).

Example 25

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydrofuran-3S-yl) ester.

Powdered anhydrous potassium carbonate (34 mg, 0.32 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (250 mg, 0.55 mmol) in dry DMF (10 ml). The mixture was stirredunder nitrogen for fifteen minutes. Methanesulfonic acid2-oxo-tetrahydro-furan-3R-yl ester (Intermediate 4, 99 mg, 0.55 mmol)was then added and the mixture stirred for ten minutes. The solution waspartitioned between saturated sodium bicarbonate solution (50 ml) andethyl acetate (50 ml), washed with 2M hydrochloric acid solution (50ml), dried and evaporated to a solid. The crude product was purified byflash chromatography on silica gel, eluting with ethylacetate-cyclohexane (1:1) followed by ethyl acetate-cyclohexane (3:1) toafford the title compound as a white solid (148 mg, 50%): mp. 310-314°C.; MS (ES+ve) m/z 539 [MH]⁺; NMR δ (CDCl₃) includes 7.14 (1H, dd, J 10and 1 Hz), 6.44 (1H, s), 6.38 (1H, dd, J 10 and 1 Hz), 5.49 and 5.29(1H, 2m), 5.01 (1H, d, J 4 Hz), 4.58-4.30 (4H, m), 1.53 (3H, s), 1.44(3H, s), 1.25 (3H,s), 1.02 (3H, s). This compound is identical withisomer A of Example 12.

Example 26

6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3R-yl) ester.

Powdered anhydrous potassium carbonate (34 mg, 0.32 mmol) was added to astirred solution of6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid (250 mg, 0.55 mmol) in dry DMF (10 ml). The mixture was stirredunder nitrogen for thirty minutes. Methanesulfonic acid2-oxo-tetrahydro-furan-3S-yl ester (Intermediate 5, 99 mg, 0.55 mmol)was then added and the mixture stirred for fifteen minutes. The solutionwas partitioned between saturated sodium bicarbonate solution (50 ml)and ethyl acetate (50 ml), washed with 2M hydrochloric acid solution (50ml), dried and evaporated to a solid. The crude product was purified byflash chromatography on silica gel, eluting with ethylacetate-cyclohexane (1:1) followed by ethyl acetate-cyclohexane (3:1) toafford the title compound as a white solid (120 mg, 41%): mp. 284-287°C.; MS (ES+ve) m/z 539 [MH]⁺; NMR δ (CDCl₃) includes 7.13 (1H, dd, J 10and 1 Hz), 6.43 (1H, s), 6.38 (1H, dd, J 10 and 1 Hz), 5.48 and 5.28(1H, 2m), 4.97 (1H, d, J 4 Hz), 4.60 (1H, J 9 and 3 Hz), 4.45-4.3 (2H,m), 3.91 (1H, t, J 10 Hz), 1.53 (3H, s), 1.45 (3H, s), 1.27 (3H,s), 0.96(3H, s). This compound is identical to isomer B of Example 12.

Example 27

16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid (5-oxo-tetrahydro-furan-2-yl) ester.

Powdered anhydrous potassium carbonate (29 mg, 0.21 mmol) was added to astirred solution of16α,17α-(R-butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid (Intermediate 7, 100 mg, 0.21 mmol) in dry DMF (2 ml). The mixturewas stirred under nitrogen, γ-chloro-γ-butyrolactone (42 mg, 0.35 mmol)was added and the mixture stirred until reaction was complete asmonitored by TLC. The solution was partitioned between water (25 ml) andethyl acetate (25 ml). The organic phase was separated, washed withwater (2×25 ml), dried and evaporated to a gum. The crude product waspurified by preparative layer chromatography on silica gel, eluting withdiethyl ether to give the title compound as a foam (24 mg, 21%): MS(ES+ve) m/z 555 [MH]⁺; IR ν_(max) (KBr) 3484, 1790, 1700, 1665 cm⁻¹; NMRδ (CDCl₃) includes 6.24 (0.5H, dd, J 8 and 6 Hz), 6.15 and 6.14 (1H,2s), 5.86 (0.5H, dd J 5 and 1 Hz), 5.33 and 5.21 (1 H, 2m), 4.84 (0.5H,d, J 5.5 Hz), 4.80 (0.5H, t, J 4.5 Hz), 4.78 (0.5H, d, J 5.5 Hz), 4.71(0.5H, t, J 4.5 Hz), 4.44 and 4.38 (1H, 2m), 1.53 and 1.52 (3H, 2s),1.00-0.92 (6H, m). The individual diastereoisomers were separated byfurther preparative layer chromatography on silica gel, eluting withdiethyl ether (×3) to give the title compound isomer A as a foam (8 mg,7%): MS (ES+ve) m/z 555 [MH]⁺; NMR δ (CDCl₃) includes 6.24 (1H, t, J 7Hz), 6.14 (1H, s), 5.38 and 5.28 (1H, 2m), 4.84 (1H, d, J 5 Hz), 4.71(1H, t, J 4.5 Hz), 4.38 (1H, m), 1.52 (3H, s), 0.97 (6H, m), and thetitle compound isomer B as a foam (5 mg, 4%): IR ν_(max) (KBr) 3448,1790, 1713, 1681, 1651 cm⁻¹; NMR δ (CDCl₃) includes 6.15 (1H, s), 5.87(1H, dd, J 4 and 1 Hz), 5.38 and 5.18 (1H, 2m), 4.79 (2H, m), 4.44 (1H,m), 1.53 (3H, s), 0.98 (6H, m).

Pharmacological Activity

In Vitro

The pharmacological activity was studied in a functional in vitro assayto demonstrate glucocorticoid activity which is generally predictive ofanti-inflammatory or anti-allergic activity in-vivo.

The functional assay used was a modification of the method described byT. S Berger et al, of J. of Steroid Biochem. Molec. Biol. 1992, 41(3-8), 733-738, “Interaction of Glucocorticoid analogues with the HumanGlucocorticoid Receptor”.

Thus, Hela cells were stably transfected with a detectable reporter gene(secreted placental alkaline phosphatase, sPAP) under the control of aglucocorticoid response promoter (the LTR of the mouse mammary tumourvirus, MMTV).

Various concentrations of standard (dexamethasone) or compounds of theinvention were incubated with transfected Hela cells for 72 hours. Atthe end of the incubation, substrate (p-nitrophenol acetate) for sPAPwas added and the product measured by a spectrophotometric method.Increased absorbance reflected increased sPAP transcription andconcentration-response lines were constructed such that EC₅₀-valuescould be estimated.

In this test, the isomers of Examples 1, 4, 5, 6, 7, 8, 12, 15, 16, 19,22, 23 and 24 and the compound of Example 9 had EC₅₀-values of less than400 nM.

Hydrolysis in Blood

All the isomer/compounds of the Examples were unstable in human plasmaindicating that they are expected to possess an advantageous in vivoside effect profile. Compounds of examples 15, 16, 22 and 23 showedhalf-lives of less than 3 h whilst all isomers in the remaining examplesshowed half-lives of less than 60 min.

In Vivo

(i) Anti-inflammatory Activity—Inhibition of rat ear oedema

The test compounds are dissolved in acetone and 40 ul containing 5%croton oil is applied to the inner surface of each of the ears of 60-80g male rats. Animals are killed 6 hours later and the ears are removed.Standard size (0.5 cm diameter) discs are punched out and the discsweighed. Mean weight of the ear discs is calculated and from thispercentage inhibition of ear inflammation in relation to croton oilalone treated ears are calculated.

Compound Dose % Inhibition Example 2 100 μg 42 Example 19 Isomer A 100μg 54 Example 19 Isomer B 100 μg 43 Example 16 Isomer B 10 μg 42

(ii) Systemic effects—ACTH suppression in adrenalectomised rats

Male CD rats (90-120 g) were adrenalectomised under Isofluraneanaesthesia and drinking water was supplemented with 0.9% saline. Fourdays later the animals receive a single intra-tracheal dose (underIsoflurane anaesthesia) of compound suspended in saline (containing 0.2%Tween-80, 0.2 ml) at 10 am. After 4 h animals are sacrificed byadministration of Euthetal and blood samples are taken by intra-cardiacpuncture and collected into heparinised tubes. The samples arecentrifuged (20 minutes at 1000 RPM at 4 deg C.), the plasma iscollected and assayed by Radioimmunoassay (RIA) for Adrenocorticotrophichormone (ACTH) using a DPC double antibody RIA kit. Intact and vehiclecontrol groups were included in each experiment in order to account fordiurnal variation in ACTH and effects of vehicle. Results are calculatedwith respect to the RIA standard curve and expressed as ACTH pg/mlplasma, allowing percentage reduction in ACTH to be calculated.

Compound Dose % Reduction in ACTH Fluocinolone acetonide 1 μg 49Fluocinolone acetonide 5 μg 84 Example 2 500 μg  0

This result illustrates the minimal systemic activity associated withthese plasma labile derivatives.

Pharmaceutical Formulations

The following are examples of suitable formulations of compounds of theinvention. The term “active ingredient” is used herein to represent acompound of the invention and can be, for example, the isomers (or amixture thereof) of Examples 1, 12 or 19.

1. Inhalation Cartridges

Active ingredient micronised 1.6% w/w Lactose BP 98.4% w/w.

The active ingredient is micronised in a conventional manner to a fineparticle size range such as to permit inhalation of substantially all ofthe medicament into the lungs upon administration, prior to blendingwith normal tableting grade lactose in a high energy mixer. The powderblend is filled into gelatin capsules on a suitable encapsulatingmachine. The contents of the cartridges are administered using a powderinhaler such as ROTAHALER™ inhaler. Alternatively, the powder blend canbe filled into blisters of a blister pack or strip. The contents of theblister pack or strip are administered using a powder inhaler such asDISKHALER™ or DISKUS™ inhaler. [ROTAHALER, DISKHALER and DISKUS aretrade marks of the Glaxo Wellcome group of companies].

2. Aerosol Formulation

(i) Suspension

mg/actuation per can Active ingredient micronised 0.25 40 mg1,1,1,2-tetrafluoroethane 74.75 11.96 g

The active ingredient is weighed directly into an open aluminium can anda metering valve is then crimped in place. 1,1,1,2-Tetrafluoroethane isthen added to the can under pressure through the valve and the canshaken to disperse the drug. The resultant inhaler contains 0.33% w/wactive ingredient.

(ii) Solution

mg/actuation per can Active ingredient micronised 0.25 40 mg Ethanol(anhydrous) 7.5 1.2 g 1,1,1,2-tetrafluoroethane 67.25 10.76 g

Active ingredient is dissolved in the ethanol. The resultant ethanolicsolution of active ingredient is metered into an open aluminium can anda metering valve is then crimped in place. 1,1,1,2-Tetrafluoroethane isthen added under pressure through the valve. The resultant inhalercontains 0.33% w/w active ingredient and 10% w/w ethanol.

3. Cream

% w/w Active ingredient micronised 0.2 Liquid Paraffin 40 Cetostearylalcohol 5 Cetomacrogol 1000 1 Isopropylmyristate 5 Propylene glycol 10Benzoic acid 0.2 Sodium phosphate 0.05 Citric acid/monohydrate 0.05Purified water to 100

The micronised active ingredient is dispersed in a portion of the watercontaining a portion of the cetomacrogol 1000. The liquid paraffin,cetostearyl alcohol and isopropyl myristate are melted together, cooledto 50 to 60° C. and added to the remaining water containing thepropylene glycol, benzoic acid (preservative), and sodium phosphate andcitric acid (buffering agents). The resultant oil phase is added to theactive ingredient suspension with stirring until cool.

Protection may be sought for any subject matter described herein. Thus,protection may be sought for the compounds (including intermediates),compositions, processes and uses described herein.

What is claimed is:
 1. A compound of formula (I)

and solvates thereof, in which R₁ represents O, S or NH; R₂ individuallyrepresents OC(═O)C₁₋₆ alkyl; R₃ individually represents hydrogen,methyl, which may be in either the α or β configuration or ═CH₂; or R₂and R₃ together represent

 wherein R₆ and R₇ are the same or different and each representshydrogen or C₁₋₆ alkyl; R₄ and R₅ are the same or different and eachrepresents hydrogen or halogen; and represents a single or a doublebond.
 2. A compound according to claim 1 in which R₁ represents O or S.3. A compound according to claim 2 in which R₁ represents S.
 4. Acompound according to claim 1 in which R₁ is bonded to the alpha carbonatom of the lactone moiety.
 5. A compound according to claim 1 in whichR₂ individually represents OC(═O)C₁₋₆ alkyl.
 6. A compound according toclaim 5 in which R₂ represents OC(═O)C₁₋₃ alkyl.
 7. A compound accordingto claim 5 in which R₂ represents OC(═O) ethyl.
 8. A compound accordingto claim 1 in which R₃ is methyl.
 9. A compound according to claim 1 inwhich R₂ and R₃ together represent

wherein R₆ and R₇ are the same or different and each represents hydrogenor C₁₋₆ alkyl.
 10. A compound according to claim 9 in which R₆ and R₇are the same or different and each represents hydrogen or C₁₋₃ alkyl.11. A compound according to claim 9 in which R₆ and R₇ are the same ordifferent and each represents hydrogen, methyl or n-propyl.
 12. Acompound according to claim 9 in which R₆ and R₇ are both methyl.
 13. Acompound according to claim 9 in which R₆ and R₇ are different and eachrepresents hydrogen or n-propyl.
 14. A compound according to claim 1 inwhich R₄ and R₅ are the same or different and each represents hydrogen,fluorine or chlorine.
 15. A compound according to claim 1 in which R₄and R₅ are the same or different and each represents hydrogen orfluorine.
 16. A compound according to claim 1 in which both R₄ and R₅are fluorine.
 17. A compound according to claim 1 in which R₁ is S; R₂is OC(═O)C₁₋₆ alkyl; R₃ is methyl; R₄ and R₅ are the same or differentand each represents hydrogen or fluorine; and represents a single or adouble bond.
 18. A compound according to claim 17 in which R₂ is OC(═O)ethyl and R₄ and R₅ are each fluorine.
 19. A compound according to claim1 in which R₁ is S; R₂ and R₃ together represent

wherein R₆ and R₇ are the same or different and each represents hydrogenor C₁₋₆ alkyl; R₄ and R₅ which can be the same or different eachrepresents hydrogen or fluorine, and represents a single or a doublebond.
 20. A compound according to claim 19 in which R₆ and R₇ are thesame or different and each represents hydrogen, methyl or n-propyl; andR₄ and R₅ are each fluorine. 21.17α-Butyryloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;17α-Acetyloxy-6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;9α-Fluoro-11β-hydroxy-16β-methyl-3-oxo-17α-propionyioxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(5-oxo-tetrahydro-furan-2-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-4-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-5-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-5-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide;6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;16α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;16α,17α-Butylidenedioxy-11β-hydroxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid (2-oxo-tetrahydro-furan-3-yl) ester;16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-3-yl) amide;6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carboxylicacid N-(2-oxo-tetrahydro-furan-4-yl) amide;6α,9α-Difluoro-11β-hydroxy-16-methyl-3-oxo-17α-propionyloxy-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester;16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid (5-oxo-tetrahydro-furan-2-yl) ester; and solvates thereof. 22.6α,9α-Difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; and solvates thereof. 23.6α,9α-Difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; and solvates thereof. 24.16α,17α-(R-Butylidenedioxy)-6α,9α-difluoro-11β-hydroxy-3-oxo-androst-4-ene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; and solvates thereof.
 25. Apharmaceutical composition comprising a compound of formula (I) asdefined in claim 1 or a physiologically acceptable solvate thereoftogether, if desirable, in admixture with one or more physiologicallyacceptable diluents or carriers.
 26. A method for the treatment of ahuman or animal subject with an anti-inflammatory and/or allergiccondition, which method comprises administering to said human or animalsubject an effective amount of a compound of formula (I) as defined inclaim 1 or a physiologically acceptable solvate thereof.
 27. A processfor the preparation of a compound of formula (I) as defined in claim 1,which comprises A) treating a compound of formula (II)

 in which R₂, R₃, R₄, R₅ and are as defined in claim 1 for compounds offormula (I) and X represents OH or an activated derivative thereof, witha compound of formula (III)

 and salts thereof, in which Z represents OH, NH₂ or SH; B) forcompounds of formula (I) wherein R₁ represents O or S, treating acompound of formula (II) in which R₂, R₃, R₄, R₅ and are as defined inclaim 1 for compounds of formula (I) and X represents OH or SH or theircorresponding salts, with a compound of formula (VI) or formula (VII)

in which Q represents a suitable Cl, Br or OSO₂A group, wherein A isCH₃, CF₃ or p-CH₃C₆H₄; C) conversion of a compound of formula (I) to atransacetylated, epimerized or esterified compound of formula (I); or D)deprotecting a hydroxyl protected derivative of a compound of formula(I), optionally followed by (i) solvate formation of (ii) preparation ofan individual isomer of a compound of formula (I).